Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole

ABSTRACT

An oral pharmaceutical composition comprises an acid-labile irreversible proton pump inhibitor in pellet or tablet form, wherein the irreversible proton pump inhibitor is at least partly in slow-release form. On combined administration with an anti-microbially-active ingredient, the composition is distinguished by imparting an enhanced action of rapid onset against disorders caused by Helicobacter.

RELATED APPLICATION

This application is a continuation of application Ser. No. 09/042,090,filed Mar. 13, 1998 U.S. Pat. No. 6,068,856, which is a division ofapplication Ser. No. 08/498,386 (now U.S. Pat. No. 5,945,124), filedJul. 5, 1995, and is related to Applicants' application Ser. No.08/498,391, filed Jul. 5, 1995 U.S. Pat. No. 6,132,768.

FIELD OF THE INVENTION

The present invention relates to oral pharmaceutical compositions inpellet or tablet form for combined use of pantoprazole with anantimicrobially-active ingredient for the treatment of disorders causedby Helicobacter.

BACKGROUND

Pyridin-2-ylmethylsulfinyl-1H-benzimidazoles, as disclosed, for example,in EP-A 0005129, EP-A 0166287 and EP-A 0268956 are becoming increasinglyimportant, because of their H⁺/K⁺ ATPase-inhibiting action, for thetherapy of diseases which originate from increased gastric acidsecretion. Examples of active ingredients which are already commerciallyavailable from this group are omeprazole (INN), lansoprazole (INN) andpantoprazole (INN). These active ingredients are also called acid-labileirreversible proton pump inhibitors.

Control of the microbe, Helicobacter pylori, which is thought to beresponsible for certain gastric disorders, by combined use of anantimicrobially-active ingredient which is active against Helicobacterpylori and of an agent which reduces gastric acid has been regarded asthe method of choice for some time.

EP-A 0519365 proposes (for the active ingredient pantoprazole) aformulation based on the principle of an alkaline core coated with awater-soluble intermediate layer and with an enteric layer, whereimproved stability is achieved by using polyvinylpyrrolidone and/orhydroxypropylmethylcellulose as binder for the alkaline core.

EP-A 0342522 discloses a formulation for acid-sensitive benzimidazoles,in which an intermediate layer is located between the alkaline core andthe enteric coating and is composed of a film-forming material which hasonly low solubility in water, such as ethylcellulose and polyvinylacetate, and of a fine-particle inorganic or organic material which issuspended therein and has low solubility in water, such as magnesiumoxide, silicon oxide or sucrose fatty acid esters.

JP-A 59020219 discloses an enteric composition for acid-labile activeingredients which comprises (under the enteric coating) an intermediatelayer of a film-forming material, such as hydroxypropylmethylcellulose,hydroxypropylcellulose and hydroxypropylmethylcellulose phthalate with acontent of higher fatty acids.

DE-A 3233764 proposes for enteric composition an intermediate layerwhich is formed from a water-soluble cellulose ether and a water-solublemono- or polybasic organic acid, such as citric acid, tartaric acid, andthe like.

Combined use of irreversible proton pump inhibitors withantimicrobially-active ingredients does indeed show a good effectagainst Helicobacter in vitro. However, the clinical effect achievedwith this combined use is disappointing. Of practical inconvenience isthe great delay in the onset of action.

SUMMARY OF THE INVENTION

The action of an antimicrobially-active ingredient on Helicobactersurprisingly is enhanced by administering pantoprazole in slow-releasedosage form (extended release form). It must be regarded as particularlysurprising that, in addition, administration of the slow-releasepantoprazole results in the onset of action taking place significantlyfaster than on administration in a form without retarding such release.The duration of treatment until Helicobacter is eradicated is shortened,saving considerable amounts of antibiotic and acid inhibitor.

The invention thus relates to oral pharmaceutical compositions in pelletor tablet form for combined use of pantoprazole with anantimicrobially-active ingredient for treatment of disorders caused byHelicobacter, wherein pantoprazole is present at least partly inslow-release form.

The invention also relates to an oral pharmaceutical composition inpellet or tablet form for acid-labile irreversible proton pumpinhibitors comprising an alkaline pellet or tablet core, at least onerelease-slowing, release-controlling intermediate layer and an outerenteric layer which is soluble in the small intestine, wherein theintermediate layer for the pharmaceutical composition is formed from awater-insoluble film former, the film former being applied fromanhydrous solution or aqueous dispersion.

As noted in the Background, commercially available acid-labileirreversible proton pump inhibitors other than pantoprazole, such asomeprazole (INN) and lansoprazole (INN), are known.

DETAILS

In connection with the present invention, pantoprazole is the compound,5-difluoromethoxy-2-[(3,4-dimethoxy-2-pyridinyl)methylsulfinyl]-1H-benzimidazole,its salts and solvates (e.g. hydrates), in particular the sodium saltwith one and a half molecules of water of crystallization (pantoprazoleNa×1.5 H₂O).

Examples of suitable antimicrobially-active ingredients (active againstHelicobacter and, in particular, against Helicobacter pylori) areenumerated in European Patent Application EP-A 0282131. These activeingredients include, for example, bismuth salts (such as bismuthsubcitrate or bismuth subsalicylate), sulfonamides, nitrofurans (such asnitrofurazone, nitrofurantoin or furazolidone), metronidazole,tinidazole, nimorazole or antibiotics. Examples of antibiotics which maybe mentioned in this connection are, arranged according to particularclasses of active ingredient: aminoglycosides, such as gentamicin,neomycin, kanamycin, amikacin or streptomycin; macrolides, such aserythromycin, azithromycin, clarithromycin, clindamycin or rifampicin;penicillins, such as penicillin G, penicillin V, ampicillin, mezlocillinor amoxicillin; polypeptides, such as bacitracin or polymyxin;tetracyclines, such as tetracycline, chlorotetracycline,oxytetracycline, minocycline or doxycycline; carbapenems, such asimipenem, loracarbef, meropenem or panipenem; cephalosporins, such ascefalexin, cefoxitin, cefuroxime axetil, cefotaxime, cefpodoximproxetil, cefaclor, cefadroxil or cephalothin; gyrase inhibitors, suchas ciprofloxacin, norfloxacin, ofloxacin or pefloxacin, or otherdifferent antibiotics, such as chloramphenicol.

Particularly worth of mention in this connection is also the conjointadministration of pantoprazole with a plurality ofantimicrobially-active ingredients, for example with a combination ofbismuth salt and/or tetracycline with metronidazole, or with thecombination of amoxicillin or clarithromycin with metronidazole.

Antimicrobially-active ingredients which may be emphasized areerythromycin, azithromycin, clarithromycin, clindamycin, rifampicin,ampicillin, mezlocillin, amoxicillin, tetracycline, minocycline,doxycycline, imipenem, meropenem, cefalexin, cefuroxime axetil,cefpodoxime proxetil, cefaclor, cefadroxil, ciprofloxacin, norfloxacin,ofloxacin and pefloxacin.

Clarithromycin and amoxicillin may be mentioned asantimicrobially-active ingredients which should be particularlyemphasized.

Combined administration means, for the purpose of the present invention,fixed and, in particular, free combinations, i.e. either slow-releasepantoprazole and the antimicrobially-active ingredient are presenttogether in one dosage unit, or slow-release pantoprazole andantimicrobially-active ingredient, which are present in separate dosageunits, are administered in direct succession or at a relatively largetime interval; a relatively large time interval means a time span up toa maximum of 24 hours. For use as separate dosage units, these arepreferably made available together in one pack. For example, the twodosage units are packed together in blister packs which are designedwith regard to the relative arrangement of the two dosage units withrespect to one another, the inscription and/or coloring in a mannerknown per se so that the time for taking the individual components(dosage regimen) of the two dosage units are evident to a patient.

A dosage unit means, in particular, a medicinal dosage form in whichslowing of pantoprazole release is achieved with as few problems aspossible. This includes, in particular, tablets, coated tablets orpellets, and microtablets in capsules, with the dosage formadvantageously being designed so that the two active-ingredientcomponents (pantoprazole on the one hand and antimicrobially-activeingredient on the other hand) are released, or made availableeffectively for the body, in such a way that an optimal activeingredient profile, and thus action profile, is achieved.

It is possible to use (for retarding release) various types and degreesof retardation so that a pantoprazole plasma level, which persists aslong as possible and is sufficient for raising pH, is ensured.

The pharmaceutical formulation of the antimicrobially-active ingredientis carried out as is familiar per se to the skilled worker for theindividual active ingredient.

Rapid release of part of the pantoprazole and extending release ofanother part can be achieved, for example, also by layered tablets ormultilayer tablets, in which case part of the pantoprazole is present inan outer coating in a form without retarding its release; this isfollowed by another coating containing the antimicrobially-activeingredient and then the core with the pantoprazole, whose release isextended in a suitable manner.

The details of how to achieve slowing of or extending release arefamiliar to the skilled worker on the basis of his expert knowledge. Theskilled worker is likewise familiar with suitable ancillary substancesand vehicles for the required dosage forms (pharmaceuticalformulations). Besides solvents, tablet auxiliary substances and otheractive ingredient excipients it is possible to use, for example,tablet-coating compositions, plasticizers, antioxidants, preservatives,dyes, etc. Where incompatibilities between the active ingredients orbetween the active ingredients and ancillary substances are expected,suitable separating layers are provided where appropriate (for examplein layered or multi-layer tablets).

The dosage of the active ingredients depends greatly on the nature ofthe antimicrobially-active ingredients used. A typical dosage forpantoprazole can be regarded as being a daily dose of from about 0.01 toabout 20, preferably from 0.05 to 5, in particular from 0.1 to 1.5,mg/kg of body weight, where appropriate in the form of a plurality ofsingle doses. Penicillins, such as amoxicillin, are administered in adaily dose of from about 5 to 40, preferably from 10 to 20, mg/kg ofbody weight.

Because of a great tendency to decompose in a neutral and, inparticular, acidic environment, which also results in highly coloreddecomposition products, for oral compositions, it is necessary on theone hand to keep pantoprazole in an alkaline environment and, on theother hand, to protect it from exposure to acids. It is generally knownto coat tablets or pellets which contain an acid-labile activeingredient with an enteric coating which, after passage through thestomach, rapidly dissolves in the alkaline medium in the intestine. Inthe case of pantoprazole, which is very acid-labile, it is necessary toprocess it in the tablet core or in pellets in the form of its alkalinesalts, for example as sodium salts, or together with alkalinesubstances. Since the substances suitable for enteric coatings containfree carboxyl groups, a problem arises when the enteric coating ispartly or even completely dissolved from the inside because of thealkaline medium in the interior, and the free carboxyl groups promotedecomposition of the active ingredients. It is therefore necessary toprovide a sealing intermediate layer (subcoating) between the entericcoating and the alkaline tablet core. EP-A 0244380 proposes to coatcores which contain the active ingredient together with alkalinecompounds or as alkaline salt with at least one layer, which is solublein water or rapidly disintegrates in water, of nonacidic, inertpharmaceutically-acceptable substance before the enteric layer isapplied.

The intermediate layer or intermediate layers act as pH-buffering zonesin which hydrogen ions, which diffuse in from the outside, are able toreact with the hydroxyl ions which diffuse out of the alkaline core. Inorder to increase the buffer capacity of the intermediate layer, it isproposed to incorporate buffer substance into the intermediate layer(s).It is possible in practice by this method to obtain rather stablecompositions. However, relatively thick intermediate layers are requiredto prevent the unsightly discoloration which occurs even on only slightdecomposition. In addition, considerable effort must be made to avoidtraces of moisture during manufacture.

It is a further aim within the scope of the present invention to providean oral pharmaceutical composition with delayed and controlled releaseof active ingredients in pellet or tablet form for pantoprazole, whichis distinguished by great resistance to decomposition and discolorationof the active ingredient caused by moisture and other effects.

This aim is particularly advantageously achieved by providing at leastone release-slowing intermediate layer of water-insoluble film former,which at the same time represents a barrier for mutual interactionsbetween the active ingredient with an alkaline reaction and the entericcoating with an acidic reaction.

In this connection, film formers are regarded as insoluble in water whenthey cannot be dissolved in water without further additions (organicsolvents, detergents, alkalizing substances, etc.).

The slowing of release can be achieved, for example, by a semipermeablemembrane, as disclosed in numerous patents (e.g. EP B 0185331).

The details of how to achieve slowing of release are familiar to theskilled worker on the basis of his expert knowledge. The skilled workeris likewise familiar with suitable ancillary substances and vehicles forthe required dosage forms (pharmaceutical formulations). Besidessolvents, tablet ancillary substances and other active ingredientexcipients it is possible to use, for example, tablet-coatingcompositions, plasticizers, antioxidants, preservatives, dyes, etc.Where incompatibilities between the active ingredients or between theactive ingredients and ancillary substances are expected, suitableseparating layers are provided where appropriate.

The oral pharmaceutical compositions according to the invention aredistinguished from the prior art by controlled release of activeingredients and increased stability. It is particularly advantageous tokeep the intermediate layer (which controls the release of activeingredients) very thin (between 20 and 80, preferably between 40 60,μm), which leads to a considerable saving of material and shorterprocessing times. The insolubility of the intermediate layer in watermeans that the application of the enteric layer in the form of aqueoussuspensions is not critical because there can be no dissolution of theintermediate layer. Furthermore, oral pharmaceutical compositions with aconsiderably smoother surface are obtained, which not only leads to abetter visual appearance but also technically simplifies an imprintingprocess for tablets.

For a basic reaction of the pellet or tablet core it is mixed (whererequired increase in pH is not achieved simply by using anactive-ingredient salt) with an inorganic base. Mention may be made inthis connection of, for example, the pharmacologically-suitablealkali-metal, alkaline-earth-metal or earth-metal salts of weak acidsand the pharmacologically-suitable hydroxides and oxides ofalkaline-earth and earth metals. Sodium carbonate may be mentioned as abase to be emphasized by way of example.

Besides filler and binder, other ancillary substances, in particularlubricants and nonstick agents, and tablet disintegrants, are used inthe manufacture of the tablet cores. A suitable binder is, inparticular, polyvinylpyrrolidone in various degrees of polymerization.Examples of lubricants and nonstick agents which may be mentioned arehigher fatty acids and their alkali-metal and alkaline-earth-metalsalts, such as calcium stearate. Suitable tablet disintegrants are, inparticular, chemically inert agents. Tablet disintegrants which may bementioned as preferred are crosslinked polyvinylpyrrolidone, crosslinkedsodium carboxymethylcelluloses and sodium starch glycolate.

Examples of film-forming polymers which can be used in thewater-insoluble release-slowing intermediate layer(s) (to be applied tothe pellet or tablet core) include ethylcellulose, polyvinyl acetate,Eudragit® RS, Eudragit® RL, etc. (Each of Eudragit® RS and Eudragit® RLis an ammonia methacrylate copolymer.) The release rate can becontrolled not only by incorporating therein suitable water-soluble poreformers, such as PEG, lactose, mannitol, sorbitol, HPMC, etc., but alsoby the thickness of the coating layer applied.

The solvents or dispersants used for the release-controlling polymerdispersion are non-aqueous organic solvents, such as alcohols, ketonesor halogenated hydrocarbons or mixtures of such solvents.

It is possible in a similar way to use osmotic systems withsemipermeable membranes of cellulose acetate, cellulose acetatebutyrate, cellulose acetate propionate, as described in U.S. Pat. No.3,845,770, U.S. Pat. No. 3,916,899, U.S. Pat. No. 4,036,227, U.S. Pat.No. 4,093,708, U.S. Pat. No. 4,096,238, U.S. Pat. No. 4,135,514 and U.S.Pat. No. 4,142,526, to control the release of active ingredients. Thesecan be coated with aqueous dispersions of enteric lacquers withoutchanging release rate.

Examples of suitable polymers for the enteric coating are methacrylicacid/methyl methacrylate copolymer or methacrylic acid/ethylmethacrylate copolymers (Eudragit® L) or cellulose derivatives, such ascarboxymethylethylcellulose (CMEC, Duodcel), cellulose acetate phthalate(CAP), cellulose acetate trimellitate (CAT),hydroxypropylmethylcellulose phthalate (HP50, HPSS),hydroxypropylmethylcellulose acetate succinate (HPMCAS) or polyvinylacetate phthalate, to which it is also possible to add, if desired,plasticizer (such as propylene glycol) and/or other additives andancillary substances (e.g. buffers, bases, such as, preferably, aluminumhydroxide, or pigments).

The layers are applied in conventional ways using equipment customaryfor these purposes.

EXAMPLES

The following formulation examples explain the invention in detailwithout restriction it.

Example 1

Tablets:

I. Production of Uncoated Core:

a) Pantoprazole Na × 1.5 H₂O 45.1 mg b) Sodium carbonate 10.0 mg c)Mannitol 20.0 mg d) EPMC 2910 3 cps 25.0 mg e) HPMC 2910 15 cps 4.0 mgf) Calcium stearate 2.1 mg 106.2 mg

a) is mixed with one part of b), c) and d). The remainder of b) and c)is added to the clear aqueous solution of e), and the pH is adjustedto >10 with b). This solution is used for fluidized bed granulation. Theremainder of d) and f) is added to the dried granules, and the granulesare compressed in a suitable tabletting machine.

II. Release-Slowing Layer

g) Ethylcellulose 9.85 mg h) Lactose micronized 2.37 mg i) Propyleneglycol 0.98 mg j) Ammonia 25% 0.80 mg 14.00 mg

g) is dissolved in 165 ml of isopropanol to prepare solution (A). A finesuspension of h) in 165 ml of isopropanol is prepared using arotor-stator agitator, and subsequently i) and j) are stirred in using asuitable agitator to prepare suspension (B). The solution (A) and thesuspension (B) are combined.

The tablet cores obtained from I are coated to an adequate layerthickness with the suspension obtained above in suitable apparatus.

III. Enteric Coating:

l) Eudragit ® L 13.64 mg m) Triethyl citrate 1.36 mg 15.00 mg

l) is diluted with 140 ml of water, and m) is added. The resultingdispersion is screened before processing. The dispersion from III issprayed onto the presealed cores obtained from II in suitable equipment.

Example 2

Tablets:

I. Production of the Uncoated Core:

Production of the cores took place as in Example I point I.

II. Release-Slowing Layer:

g) Polyvinyl acetate 9.15 mg h) Lactose micronized 2.27 mg i) Propyleneglycol 0.91 mg j) Ammonia 25% 0.80 mg 13.13 mg

g) is dissolved in 150 ml of 1:1 acetone/chloroform mixture to prepare asolution (A).

A fine dispersion of h) in 150 ml of 1:1 acetone/chloroform mixture isprepared using a rotor-stator agitator, and subsequently i) and j) arestirred in using a suitable agitator to prepare a suspension (B).Solution (A) and suspension (B) are combined.

The tablet cores obtained in I are coated to a sufficient layerthickness with the suspension obtained above in suitable apparatus.

III. Enteric Coating:

l) Eudragit ® L 13.46 mg m) Triethyl citrate 1.36 mg 15.00 mg

Total weight per enteric film-coated tablet 183.50 mg

l) is diluted with 135 ml of water, and m) is added. The dispersion isscreened before processing.

The dispersion from III is sprayed onto the presealed cores obtained inII in suitable equipment.

Example 3

Pellets:

I. Starter Pellets

a) Sucrose pellets (0.7-0.85 mm) 950.0 g b) Hydroxypropylmethylcellulose40.0 g 2910 (USP) c) Propylene glycol 9.9 g d) NaOH 0.1 g

a) is sprayed with an aqueous solution of b), c) and d) in a fluidizedbed (Wurster method).

II. Active Pellets

e) Pantoprazole Na × 1.5 H 403.0 g f) Hydroxypropylmethylcellulose 403.0g 2910 (USP) g) Propylene glycol 201.5 g h) NaOH 1.0 g

f), g), h), e) are successively dissolved in 4 liters of purified waterand sprayed onto 900 g of the pellets obtained in I in a fluidized bed(Wurster method).

III. Presealed Pellets

A release-slowing layer is applied in analogy to the procedure describedfor tablets in a pan or fluidized bed.

IV. Enteric-Coated Pellets

The coating is applied in analogy to the procedure described for thetablets in a pan or fluidized bed.

The pellets are subsequently packed into capsules of suitable size (e.g.size 1).

Example 4

Pellets:

I. Active Pellets

c) Pantoprazole Na × 1.5 H₂O 403.0 g d) Na carbonate 87.3 g e)Microcyrstalline cellulose 117.0 g (Avicel PH101) f) Nacarboxymethylcellulose 18.0 g

c)-f) are premixed dry and subsequently moistened to a paste-likeconsistency with a solution of Na carbonate and Nacarboxymethylcellulose in water in a conventional kneader or high-speedmixer. The resulting composition is then extruded and shaped intopellets by the extruder/rounder method familiar to the skilled worker.The moistened pellets are dried in suitable equipment (drying oven,fluidized bed, etc.).

III. Release-Slowing Layer:

The release-slowing layer is applied in analogy to the proceduredescribed for tablets in a pan or fluidized bed.

IV. Enteric-Coated Pellets

The coating is applied in analogy to the procedure described for tabletsin a pan or fluidized bed.

The pellets are subsequently packed into capsules of suitable size (e.g.size 1).

The invention and its advantages are readily understood from theforegoing description. As is apparent, various changes can be made inthe products and methods without departing from the spirit and scope ofthe invention or sacrificing its material advantages. The products andprocesses hereinbefore described are merely illustrative of preferredembodiments of the invention.

We claim:
 1. An oral pharmaceutical composition in pellet or tablet formwith delayed and controlled release of active ingredient, comprising anacid-labile irreversible proton pump inhibitor other than pantoprazole,and wherein the composition comprises an alkaline pellet or tablet core,at least one intermediate layer controlling release of active ingredientand an outer enteric layer which is soluble in the small intestine.
 2. Aprocess for producing an oral pharmaceutical composition in pellet ortablet form for omeprazole or lansoprazole, as active ingredient, whichcomprises a) incorporating the active ingredient as an alkaline saltand/or with addition of an alkaline substance in a pellet or tabletcore, b) applying thereto at least one release-slowing intermediatelayer comprising a water-insoluble, release-slowing film former and c)subsequently applying an outer enteric layer which is soluble in thesmall intestine.
 3. A process as claimed in claim 2, wherein thewater-insoluble, release-slowing film former for the intermediate layeris applied in solution or dispersion form.
 4. An oral pharmaceuticalcomposition as claimed in claim 1, wherein the acid-labile irreversibleproton pump inhibitor is omeprazole.
 5. An oral pharmaceuticalcomposition as claimed in claim 1, wherein the acid-labile irreversibleproton pump inhibitor is lansoprazole.
 6. An oral pharmaceuticalcomposition in pellet or tablet form with delayed and controlled releaseof active ingredient and comprising an acid-labile irreversible protonpump inhibitor other than pantoprazole, and wherein part of the protonpump inhibitor is in a controlled (extended) release form and part ofthe proton pump inhibitor is in a form without retarding its release(rapid release form).
 7. An oral pharmaceutical composition as claimedin claim 1, wherein at least one intermediate layer is formed from awater-insoluble, release-slowing film former.
 8. An oral pharmaceuticalcomposition as claimed in claim 7, wherein the film former is one whichhas been applied from a solution or dispersion.
 9. An oralpharmaceutical composition as claimed in claim 7, wherein theintermediate layer contains, as water-insoluble, release-slowing filmformer, water-insoluble cellulose ether and/or polyvinyl acetate.
 10. Anoral pharmaceutical composition as claimed in claim 7, wherein theintermediate layer contains, as water-insoluble, release-slowing filmformer, ethylcellulose or polyvinyl alcohol.
 11. An oral pharmaceuticalcomposition as claimed in claim 7, wherein the outer enteric layer,which is soluble in the small intestine, comprises methacrylicacid/methyl methacrylate copolymer or methacrylic acid/ethylmethacrylate copolymer.
 12. An oral pharmaceutical composition asclaimed in claim 1, wherein the outer enteric layer comprises acellulose-based coating.
 13. An oral pharmaceutical composition asclaimed in claim 12, wherein the cellulose-based coating is a memberselected from the group consisting of carboxymethylethylcellulose,cellulose acetate phthalate, cellulose acetate trimellitate,hydroxypropylmethylcellulose phthalate and ahydroxypropylmethylcellulose acetate succinate.
 14. An oralpharmaceutical composition as claimed in claim 1, wherein theintermediate layer further comprises a member selected from the groupconsisting of a pore former, plasticizer, buffer, base and pigment. 15.An oral pharmaceutical composition in pellet or tablet form comprisingan acid-labile irreversible proton pump inhibitor and having an alkalinepellet or tablet core, at least one release-slowing, release-controllingintermediate layer and an outer enteric layer which is soluble in thesmall intestine, wherein the intermediate layer comprises awater-insoluble film former.
 16. A process as claimed in claim 3,wherein the solution or dispersion is in a non-aqueous organic solvent.17. An oral pharmaceutical composition as claimed in claim 6, whereinthe acid-labile irreversible proton pump inhibitor is omeprazole orlansoprozole.